Liposomes as drug carriers have shown a wide range of therapeutic applications particularly for those disease states where macrophages are the target of pharmacological intervention. Developmental efforts have been, however, greatly hampered from the lack of pharmaceutical technology of producing a stable suspension product for systemic administration. For instance, increase in size during storage can not only alter the pharmacokinetic disposition of the drug entrapped in liposomes upon IV administration but also bring about embolism in a capillary blood vessel. In addition, drug molecules entrapped should not leak out during storage. Some molecular events requisite to vesicle fusion, an important cause for both phenomena, can be stopped if liposomes are polymerized after being produced. However,lipids of polymerized vesicles developed thus far may not be degraded completely by lysosomal enzymes of macrophages after phagocytosis and may remain as residual bodies for a long period of time. The present proposal will test a feasibility of developing crosslinked liposomes which are devoid of the aforementioned stability-related problems and yet biodegradable once internalized in the phagocytic target cell. We propose to synthesize two phospholipid derivatives which would form liposomes with or without other naturally occurring lipids and at the same time allow us to crosslink the resulting liposomes by simple chemical manipulations. The resulting liposomes will be characterized in terms of size determined by photon correlation spectroscopy, permeability of entrapped [14C]-sucrose, biochemical stability in the presence of lysosomal enzymes of J774 macrophage-derived cells, morphology characterized by various electron microscopic techniques, and thermal behavior determined by differential scanning calorimetry. An important long-term objective is to develop liposomes containing water-soluble polar antibiotics which are normally incapable of penetrating cell membranes specifically for treatment of various intracellular infectious diseases. Future studies include determination of pharmacokinetic disposition of the drug molecules entrapped in the liposomes developed in the present project at the (sub)cellular as well as organ level in animals and efficacy studies in animal disease models.